Pharmaceutical preparations and compositions

ABSTRACT

A pharmaceutical composition characterized in that it comprises 
     (a) Vitamin A, 
     (b) one or more tochopherols 
     (c) an oil of the genus prunus, and 
     (d) an oil of the genus sesamum; 
     in that the weight of each of (c) and (d) is between 5 and 75 times the weight of (a); in that the weight of each of (c) and (d) is between 4 and 125 times the weight of (b); and in that the composition has a consistency suitable for topical application.

TECHNICAL FIELD

This invention relates to pharmaceutical preparations and compositions,particularly but not exclusively for external application to providesymptomatic relief of dermatological conditions, e.g. excema, psoriasis,herpes simplex (cold sores) and the like; and their manufacture.

DISCLOSURE OF INVENTION

According to this invention there is provided a pharmaceuticalcomposition characterised in that it comprises

(a) Vitamin A,

(b) one or more tochopherols

(c) an oil of the genus prunus, and

(d) an oil of the genus sesamum,

in that the weight of each of (c) and (d) is between 5 and 75 times theweight of (a); in that the weight of each of (c) and (d) is between 4and 125 times the weight of (b); in that the composition has aconsistency suitable for topical application in that the genus prunusconsists of five members, viz. prunus communis (almond), prunusarmeniaca (apricot), prunus persica (peach), prunus domestica (plum) andprunus cerasus (cherry); and in that the genus sesamum consists of threemembers, viz. sesamum indicum, ceratotheca sesamoides and sesamumangustifoloum.

Advantageously the ratio of the weight of (a) to (b) is in the range1:15.5 to 21:1. Preferably the weight of (a) is between 0.75 and 1.8times the weight of (b).

Preferably the weights of (a) and (b) are substantially the same.

Preferably the weights of (c) and (d) are substantially the same.

Preferably the weight of (c)--or (d)--is approximately 18 to 19 timesthe weight of (a) and approximately 20 times the weight of (b).

In preferred examples of this invention, (c) comprises almond oil and(d) comprises sesame seed oil.

Advantageously said preparation or composition further comprises oliveoil, the weight of olive oil being preferably between 9 and 140 timesthe weight of (a) and/or between 7 and 250 times the weight of (b).

Preferably said Vitamin A is in the form of the resin palmitate.

BEST MODE OF CARRYING OUT THE INVENTION

Various preferred embodiments of this invention will now be described,reference being had to Table A.

In all these preferred embodiments of Table A, the Vitamin A employed isin the form of the palmitate resin oil with a strength of 1×10⁶International Units per gm of the oil. The palmitate Vitamin A alone hasa strength of 1.87×10⁶ International Units per gm whence it will beappreciated that the weight figures for constituent (a) in columns I,II, III and IV of Table A corresponds respectively 4-10, 2, 10 and 5 mlof the said palmitate resin oil.

In these preferred embodiments of Table A, the Vitamin E employedconstitutes and is provided by a mixture of tochopherols--typically10-15% alpha-tochopherols, 64-76% of a combination of beta-tochopherolsand gamma-tochopherols, and 20-30% delta-tochopherols. For the purposesof these examples, the reference to Vitamin E is to be taken as areference to the whole mixture of tochopherols employed rather than, forexample, to just the alpha-tochopherols (which are considered by someauthorities to be the essential substance to which the term Vitamin Emay be employed). For the composition of column II of Table A, theVitamin E employed was in an oil form known as T₃₀, i.e. having 300 mgof tochopherols per ml of oil, and the indicated weight of 0.6 gtherefore corresponds to 2 ml of the oil T₃₀. For the composition ofcolumn III of Table, the Vitamin E employed was in an oil form known asT₇₀, i.e. having 700 mg of tochopherols per ml of oil, and the indicatedweight of 7 g therefore corresponds to 10 ml of the oil T₇₀. For thecompositions of columns I and IV of Table A, the Vitamin E employed wasin an oil form known as T₅₀ (e.g. that sold under the Trade Mark "COVIOXT₅₀ "), i.e. having 500 mg of tochopherols per ml of oil, and theindicated weights of 2-5 g and 2.5 g therefore correspond torespectively 4-10 ml and 5 ml of the oil T₅₀.

                                      TABLE A                                     __________________________________________________________________________                 Composition                                                                   I         II    III   IV                                         Constituent  g    %    g  %  g  %  g  %                                       __________________________________________________________________________    (a) Vitamin A                                                                              2.14-5.35                                                                          1.56-2.05                                                                          1.07                                                                              0.4                                                                             5.35                                                                              4.4                                                                             2.67                                                                              1.3                                    (b) Vitamin E                                                                              2-5  1.30-1.92                                                                          0.6                                                                               0.2                                                                              7  5.7                                                                             2.5                                                                               1.2                                    (c) Almond Oil B.P.                                                                        40-60                                                                              26.0-23.1                                                                          70 24.0                                                                             30 24.5                                                                             50 24.4                                    (d) Sesame Seed Oil B.P.                                                                   40-60                                                                              26.0-23.1                                                                          70 24.0                                                                             30 24.5                                                                             50 24.4                                    (e) Olive Oil B.P                                                                           70-130                                                                            45.4-49.9                                                                          150                                                                              51.4                                                                             50 40.9                                                                             100                                                                              48.7                                    __________________________________________________________________________     Note: percentage figures shown are approximate                           

It will be appreciated that in the preferred embodiments of Table A, thealmond oil employed is an oil derived from the kernal of a fruit of thegenus prunus amygdalus variety "AMARA" or prunus amygdalus variety"DULCIS", and the sesame seed oil (or sesame oil) employed is an oilderived from the seed of the genus sesamum indicum (L. Pedaliaceae).

In forming each of the embodiments of Table A, all the constituents--inoil form--were added to one another at room temperature and mixed well.

The compositions represented by column I of Table A are preparationswith preferred ranges of the constituents (a) to (e). The composition ofcolumn II of Table A is considered to be a potentially rather weakpreparation according to this invention and yet remaining reasonablyeffective for symptomatic relief of, for example, excema. In contrast,the composition of column III of Table A is considered to be apotentially very strong and effective preparation according to thisinvention. A particularly preferred preparation according to thisinvention is the composition set out in column IV of Table A, thiscomposition being currently considered as probably the strongest onewhich would not be dangerous if taken internally by mistake.

From the approximate percentage figures given in Table A it will benoted that:

constituent (a) varies between 0.37% and 4.37%, and in preferredcomposition IV is 1.30%, of the total;

constituent (b) varies between 0.21% and 5.72%, and in preferredcomposition IV is 1.22%, of the total;

each of constituents (c) and (d) varies between 23.1% and 26.0% and inthe preferred composition IV each constitute 24.4% of the total;

and consitutent (e) varies between 40.9% and 51.4%, and in preferredcomposition IV is 48.9%, of the total. From calculations based on thesefigures it can be determined

(i) that the ratio of constituent (c) or (d) to constituent (a) isbetween 5.3 and 70.3, i.e. within the range 5 to 75 obtained byappropriate rounding up and down, and is preferably 18.8, i.e. about 18to 19,

(ii) that the ratio of constituent (c) or (d) to constituent (b) isbetween 4.0 and 123.8, i.e. within the range 4 to 125, and is preferablyabout 20,

(iii) that the ratio of constituent (a) to constituent (b) is in therange 0.06:1 to 21:1, i.e. 1:15.5 to 21:1, and is preferably in therange 0.76:1 to 1.81:1, i.e. about 0.75:1 to 1.8:1,

(iv) that this last ratio is 1.07 in the case of preferred compositionIV, i.e. the weights of constituents (a) and (b) are substantially thesame,

(v) that the ratio of constituent (e) to constituent (a) is between 9.24and 138.9, i.e. within the range 9 to 140 obtained by appropriaterounding up and down, and is 37.6 (i.e. about 37) in the case ofpreferred composition IV,

(vi) that the ratio of constituent (e) to constituent (b) is between7.15 and 244.8, i.e. within the range 7 to 250 obtained by appropriaterounding up and down, and is 40.1 (i.e. about 40) in the case ofpreferred composition IV.

For topical application the constituents (a) to (e) of each compositionmay remain in the natural oil-like state obtained by adding them to oneanother, or they may be emulsified by appropriate emulsifying agents toform a suitable or desired consistency, e.g. of a cream or of anointment.

In tests and experiments conducted to date by applying composition IV toaffected areas of the skin, remarkably positive and beneficial resultshave been noticed. The preparation has proved fast-acting, effective andlong-lasting in alleviating the irritation, itching and burningsensations usually ocurring with dermatological conditions such asexcema, psoriasis, athlete's foot, herpes simplex, heat bumps, insectbites and the like, as well as with symptoms occurring withhaemorrhoids. Moreover, a definite observed result has been experiencedin many instances where the composition appears to accelerate the body'snatural healing ability as noted by comparison of treated area healingtimes R2, R3, R4 and R7 (recorded in TABLE B below) to R8 healing timesof untreated lesions. In many cases, symptomatic relief for over 8 hourswas enjoyed from a single application of composition IV.

For example, in a pilot study along the lines of a "double blind" trial,the efficiency of composition IV of Table A was tested against

(A) cold sores, i.e. herpex simplex labialis, and

(B) minor skin irritations.

For test (A), ten volunteers with herpes simplex labialis participatedon a random basis. Eight volunteers had two lesions each and acted astheir own controls by first applying composition IV to the larger lesiononly. In all eight cases composition IV was applied to the smallerlesion after at least one week without any medication thereto. One ofthe volunteers with only one lesion agreed not to apply any medicationat all. Similarly for test (B), ten volunteers with various forms ofskin irritations participated on a random basis. All volunteers witheczema or dermatitis agreed to apply composition IV to a marked testarea alone for 7 days, thus acting as their own controls. All cases werespontaneous healing of the untreated area occurred within 7 days werediscarded. Written, informed consent was obtained from all volunteers orguardians before tests (A) and (B). The sex, age, complaint, treatmentand results associated with each volunteer are tabulated in Table B andits accompanying Notes from which it is clear that said composition IVis most efficacious against herpex simplex labialis and minor skinirritations.

                  TABLE B                                                         ______________________________________                                                             Results                                                       Volun-              Com-               Un-                                    teer                plaint                                                                              Treat-                                                                              Treated                                                                              treated                                Num-                Num-  ment  Lesion or                                                                            Lesion.sup.(1)                    Test ber     Sex    Age  ber   No.   Area   or Area                           ______________________________________                                        (A)   1      M      62   C1    T1    R3     R8                                      2      F      27   C1    T1    R3     R8                                      3      F      21   C1    T1    R4     R8                                      4      M      67   C1    T1    R3     R8                                      5      F      18   C1    T1    R3     R8                                      6      F      45   C1    T1    R4     R8                                      7      F      57   C1    T1    R3     R8                                      8      F      44   C2    T1    R3     R8                                      9      M      39   C2    T2    --     R8                                     10      F      62   C2    T3    R3     --                                (B)  11      F       3   C3    T4    R7     R8                                     12      F       5   C3    T4    R7     R8                                     13      F      54   C4    T4    R2     R8                                     14      F      34   C4    T4    R2     R8                                     15      F      18   C4    T4    R2     R8                                     16      F       2   C4    T4    R2     R8                                     17      M       7   C4    T4    R2     R8                                     18      F      11   C4    T4    R2     R8                                     19      M      24   C5    T3    R4     --                                     20      F      25   C5    T3    R3     --                                ______________________________________                                        Notes                                                                         M =   Male         T1 =    Composition IV (of Table                           F =   Female               A) applied to larger lesion                                                   immediately and to smaller                                                    lesion after 1 week.                               C1 =  2 herpes simplex                                                                           T2 =    None                                                     lesions                                                                 C2 =  1 herpex simplex                                                                           T3 =    Composition IV (of Table                                 lesions              A) applied to the 1 lesion.                        C3 =  dermatitis   T4 =    Composition IV (of Table                           C4 =  eczema               A) applied to marked                               C5 =  herpangina           test area.                                         .sup.(1) All lesions healed within                                                           R2 =    Healed after 2 days                                    5 days after treatment with                                                                  R3 =    Healed after 3 days                                    Composition IV (of Table                                                                     R4 =    Healed after 4 days                                    A) initiated.  R7 =    Healed after 3 days but                                                       relapse 4 days after                                                          treatment stopped.                                                    R8 =    Accute inflamatory changes                                                    still present after 8 days.                            ______________________________________                                    

                  TABLE C                                                         ______________________________________                                                               Efficiency against herpex                                                     simplex labialis and minor                             Test   Composition     skin irritations                                       ______________________________________                                        1.     IV of TABLE A       Very efficacious, and                                                         long-lasting relief.                               2.     2.5 g vitamin E                                                               50 g almond oil     very slight efficacy, but                                 50 g sesame oil     of reasonable duration                                    100 g olive oil                                                        3.     2.7 g vitamin A                                                               50 g almond oil     very slight efficacy, but                                 50 g sesame oil     of reasonable duration.                                   100 g olive oil                                                        4.     2.7 g vitamin A     only slight relief (of                                    2.5 g vitamin E     reasonable duration) but                                  50 g sesame oil     some burning sensation.                                   100 g olive oil                                                        5.     2.7 g vitamin A     only slight relief, of                                    2.5 g vitamin E     short duration, and                                       50 g almond oil     some burning sensation.                                   100 g olive oil                                                        6.     2.7 g vitamin A     substantial initial relief                                2.5 g vitamin E     but insufficiently                                        50 g almond oil     long-lasting.                                             50 g olive oil                                                         ______________________________________                                    

From other experimental tests conducted (see Table C) it appears thatall four constituents (a) to (d) are necessary to achieve appreciablerelief. Where one of the vitamins (A or E) is omitted from thecomposition (test 2 or 3 in Table C) the beneficial effects are severlycurtailed and only minimal relief is obtained. Omission of either almondoil or sesame seed oil (test 4 or 5 in Table C) causes a similardepreciation of the relief obtainable and leaves just a burningsensation. The trials and experiments clearly show a synergistic effectwith all four constituents (a) to (d). The provision of constituent (e),i.e. the olive oil, increases substantially the long-lasting nature ofthe relief provided by the composition. (see test 6 in Table C).

Although the reason for such a surprising synergistic effect is notknown, it is thought possible that, notwithstanding thevegetable-oil-like characteristics of constituents (c), (d) and (e), thecomposition as a whole could act as an inhibitor of the lipoxygenaseenzyme to inhibit production of inflammatory leukotrienes, i.e. thelipoxygenase metabolits of arachidonic acid (which are generally foundin vegetable oils), and which are thought to cause psoriasis and kindreddermatological disorders.

According to another aspect of this invention there is provided a methodof manufacturing a pharmaceutical composition, said method beingcharacterised in that it comprises admixing to one another:

(a) Vitamin A,

(b) one or more tochopherols

(c) an oil of the genus prunus, and

(d) an oil of the genus sesamum;

in that the weight of each of (c) and (d) is between 5 and 75 times theweight of (a); in that the weight of each of (c) and (d) is between 4and 125 times the weight of (b); and in that the composition has aconsistency suitable for topical application.

INDUSTRIAL APPLICABILITY

From the foregoing it will be appreciated that this invention is capableof widespread exploitation in the pharmaceutical and ethical chemicalindustry, and in medicine.

What is claimed is:
 1. A pharmaceutical composition characterised inthat it comprises (a) Vitamin A, (b) at least one tochopherol (c) an oilof the genus prunus, and (d) an oil of the genus sesamumin that theweight of each of (c) and (d) is between 5 and 75 times the weight of(a); in that the weight of each of (c) and (d) is between 4 and 125times the weight of (b); and in that the composition has a consistencysuitable for topical application.
 2. A pharmaceutical compositionaccording to claim 1, characterised in that the ratio of the weight ofconstituent (a) to constituent (b) is within the range 1:15.5 to 21:1.3. A pharmaceutical composition according to claim 1, characterised inthat the weight of constituent (a) is between 0.75 and 1.8 times theweight of constituent (b).
 4. A pharmaceutical composition according toclaim 1, characterised in that the weight of constituents (c) and (d)are substantially the same.
 5. A pharmaceutical composition according toclaim 1, characterised in that the weights of constituents (a) and (b)are substantially the same.
 6. A pharmaceutical composition according toclaim 1, characterised in that the weight of constituent (c) issubstanitally the same as the weight of constituent (d) and isapproximately 18 to 19 times the weight of consituent (a), andapproximately 20 times the weight of constituent (b).
 7. Apharmaceutical composition according to claim 1, characterised in thatconstituent (c) comprises almond oil.
 8. A pharmaceutical compositionaccording to claim 1, characterised in that constituent (d) comprisessesame seed oil of the species indicum.
 9. A pharmaceutical compositionaccording to claim 1, characterised in that it further comprises oliveoil.
 10. A pharmaceutical composition according to claim 1,characterised in that said Vitamin A is in the form of the resinpalmitate.
 11. A pharmaceutical composition according to claim 9,characterised in that the weight of olive oil is between 9 and 140 timesthe weight of constituent (a).
 12. A pharmaceutical compositionaccording to claim 9, wherein the weight of olive oil is between 7 and250 times the weight of constituent (b).
 13. A pharmaceuticalcomposition according to claim 9, characterised in that the weight ofolive oil is approximately 37 to 40 times the weight of each of theconstituents (a) and (b).
 14. A pharmaceutical composition characterisedin that it comprises(a) 1.0 to 5.4 parts by weight Vitamin A (b) 0.6 to7.0 parts by weight Vitamin E (c) 30 to 70 parts by weight Almond Oil(d) 30 to 70 parts by weight Sesame Seed Oil, and (e) 50 to 150 parts byweight Olive Oil;in that the weight of each of (c) and (d) is between 5and 75 times the weight of (a); in that the weight of each of (c) and(d) is between 4 and 125 times the weight of (b); and in that thecomposition has a consistency suitable for topical application.
 15. Apharmaceutical composition according to claim 14, characterised in thatit comprises(a) 2.7 parts by weight Vitamin A (b) 2.5 parts by weightVitamin E (c) 50 parts by weight Almond Oil (d) 50 parts by weightSesame Seed Oil (e) 100 parts by weight Olive Oil.
 16. A pharmaceuticalcomposition according to claim 15, characterised in that said Vitamin Ais in the form of the resin palmitate.